PRODUCT MONOGRAPH GLICLAZIDE MR - AA Pharma · Page 1 of 52 PRODUCT MONOGRAPH PrGLICLAZIDE MR...

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PRODUCT MONOGRAPH

PrGLICLAZIDE MR

Gliclazide Modified Release Tablets

30 mg

Hypoglycemic sulfonylurea - Oral antidiabetic agent AA PHARMA INC. 1165 Creditstone Road, Unit #1 Vaughan, ON L4K 4N7

Date of Preparation: June 25, 2010

Control No: 139545

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Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION ........................................................ 3 SUMMARY PRODUCT INFORMATION........................................................................ 3 INDICATIONS AND CLINICAL USE ............................................................................. 3 CONTRAINDICATIONS................................................................................................... 3 WARNINGS AND PRECAUTIONS ................................................................................. 4 ADVERSE REACTIONS ................................................................................................... 8 DRUG INTERACTIONS.................................................................................................. 15 DOSAGE AND ADMINISTRATION ............................................................................. 19 OVERDOSAGE................................................................................................................ 21 ACTION AND CLINICAL PHARMACOLOGY............................................................ 22 STORAGE AND STABILITY ......................................................................................... 27 DOSAGE FORMS, COMPOSITION AND PACKAGING............................................. 28

PART II: SCIENTIFIC INFORMATION............................................................................... 29 PHARMACEUTICAL INFORMATION ......................................................................... 29 CLINICAL TRIALS ......................................................................................................... 30 DETAILED PHARMACOLOGY .................................................................................... 34 TOXICOLOGY................................................................................................................. 37 REFERENCES.................................................................................................................. 46

PART III: CONSUMER INFORMATION ............................................................................. 50

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PrGLICLAZIDE MR

Gliclazide Modified Release Tablets PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Administration

Dosage Form / Strength

Clinically Relevant Nonmedicinal Ingredients

Oral 30 mg For a complete listing see Dosage Forms, Composition and Packaging section.

INDICATIONS AND CLINICAL USE GLICLAZIDE MR is indicated for:

Control of hyperglycemia in gliclazide responsive diabetes mellitus of stable, mild, non-ketosis

prone, maturity onset or adult type which cannot be controlled by proper dietary management

and exercise, or when insulin therapy is not appropriate.

Geriatrics (> 65 years of age): The efficacy and tolerance of GLICLAZIDE MR, prescribed using the same therapeutic regimen

in subjects over 65 years, has been confirmed in clinical trials. The dosage will therefore be

identical to that recommended for adults under the age of 65 years.

Pediatrics (< 18 years of age): Safety and effectiveness of GLICLAZIDE MR in children have not been established.

GLICLAZIDE MR is therefore not recommended for use in children and adolescents.

CONTRAINDICATIONS

GLICLAZIDE MR is contraindicated in patients with:

• Known hypersensitivity or allergy to gliclazide, other sulfonylureas, sulfonamides, or to

any of the excipients of this product. (For a complete listing see DOSAGE FORMS,

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COMPOSITION AND PACKAGING SECTION).

• Unstable and/or insulin-dependent diabetes mellitus, particularly juvenile diabetes,

diabetic ketoacidosis, diabetic pre-coma and coma.

• During stress conditions such as serious infection, trauma or surgery. In the presence of

severe liver disease or renal impairment (see WARNINGS AND PRECAUTIONS)

• Treatment with miconazole via systemic route or oromucosal gel (see DRUG-DRUG

INTERACTIONS).

• Pregnancy and lactation (see WARNINGS AND PRECAUTIONS, Special Population,

Pregnant Women and Nursing Women).

WARNINGS AND PRECAUTIONS

General

Use of GLICLAZIDE MR (gliclazide) must be considered as treatment in addition to proper

dietary regimen and not as substitute for diet.

Careful selection of patients is important. It is imperative that there be rigid attention to diet,

careful adjustment of dosage and instruction of the patient on hypoglycemic reactions, their

recognition, remedies and control as well as regular, thorough medical follow-up.

Since the effects of oral hypoglycemic agents on the vascular changes and other long-term

sequelae of diabetes mellitus are not fully known, patients receiving such drugs must be closely

observed for both short- and long-term complications. Periodic assessment of cardiovascular,

ophthalmic, renal and hepatic status is advisable.

GLICLAZIDE MR use is not recommended with medications containing alcohol,

phenylbutazone (systemic route) and danazol and precautions are required when used with

chlorpromazine, glucocorticoids, ritodrine, salbutamol, terbutaline and anticoagulant therapy (see

DRUG-DRUG INTERACTIONS).

Carcinogenesis and Mutagenesis

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See Toxicology

Endocrine and Metabolism

Hypoglycemic reactions

As with other sulfonylurea drugs, manifestations of hypoglycemia including dizziness, lack of

energy, drowsiness, headache and sweating have been observed and weakness, nervousness,

shakiness and paresthesia have also been reported. All sulfonylurea drugs can induce severe

hypoglycemia. Particularly susceptible are elderly subjects, patients with impaired hepatic or

renal function, those who are debilitated or malnourished and patients with primary or secondary

adrenal insufficiency. Some cases may be severe and prolonged. Hospitalisation may be

necessary and glucose administration may need to be continued for several days. Hypoglycemia

may be difficult to recognize in elderly patients and in patients receiving beta-blockers.

Possible other symptoms of hypoglycemia are: intense hunger, nausea, vomiting, lassitude, sleep

disorders, agitation, aggression, poor concentration, reduced awareness and slowed reactions,

depression, confusion, visual and speech disorders, aphasia, tremor, paresis, sensory disorders,

feeling of powerlessness, loss of self-control, delirium, convulsions, shallow respiration,

bradycardia, drowsiness and loss of consciousness, possibly resulting in coma and lethal

outcome. In addition, signs of adrenergic counter-regulation may be observed: clammy skin,

anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmia.

This treatment should only be prescribed if the patient is likely to have a regular food intake

(including breakfast). It is important to have a regular carbohydrate intake due to the increased

risk of hypoglycemia if a meal is taken late, if an inadequate amount of food is consumed or if

the food is low in carbohydrate. Hypoglycemia is more likely to occur during periods of low-

calorie diet, following prolonged or strenuous exercise, following alcohol intake or during the

administration of a combination of hypoglycemic agents.

Usually, hypoglycemic symptoms disappear after intake of carbohydrates (sugar). However,

artificial sweeteners have no effect. Experience with other sulphonylureas shows that

hypoglycemia can recur even when measures prove effective initially.

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If a hypoglycemic episode is severe or prolonged, and even if it is temporarily controlled by

intake of sugar, immediate medical treatment or even hospitalization are required.

Other factors which increase the risk of hypoglycemia are: overdose of GLICLAZIDE MR,

certain endocrine disorders (thyroid disorders, hypopituitarism and adrenal insufficiency) as well

as withdrawal of prolonged and/or high dose corticosteroid therapy, severe vascular disease

(severe coronary heart disease, severe carotid impairment, diffuse vascular disease) and

concomitant administration of certain medicines (See DRUG-DRUG INTERACTIONS).

Poor Blood Glucose Control:

The efficacy of gliclazide, in reducing glucose to the desired level decreases over a long period

of time in many patients: this may be due to progression in the severity of the diabetes, or to a

reduced response to treatment. This phenomenon is known as secondary failure and should be

distinguished from primary failure, when the drug is ineffective when prescribed as first-line

treatment. Adequate dose adjustment and compliance with dietary measures should be

considered before classifying the patient as secondary failure. If a loss of adequate blood

glucose-lowering response to GLICLAZIDE MR is detected, the drug should be discontinued.

Hepatic

The metabolism and excretion of sulfonylureas including GLICLAZIDE MR, may be slowed in

patients with impaired hepatic function. (See Monitoring and Laboratory Tests).

Peri-Operative Considerations

In patients stabilized on gliclazide therapy, loss of blood sugar control may occur in cases of

acute intercurrent disease or in stressful situations such as trauma or surgery. Under these

conditions, discontinuation of GLICLAZIDE MR (gliclazide) and administration of insulin

should be considered.

Renal

The metabolism and excretion of sulfonylureas including GLICLAZIDE MR, may be slowed in

patients with impaired renal function. If hypoglycemia should occur in such patients, it may be

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prolonged and appropriate management should be instituted (See Monitoring and Laboratory

Tests).

Special Populations

Pregnant Women:

Gliclazide is contraindicated in pregnancy. It is recommended that insulin be used during

pregnancy in diabetic women (See CONTRAINDICATIONS).

Uncontrolled diabetes (gestational or not) is associated with a higher incidence of congenital

abnormalities and perinatal mortality. Blood glucose control should be optimal around the time

of conception to reduce the risk of congenital malformations.

Nursing Women:

The product is contraindicated in breast-feeding mothers because the potential for hypoglycemia

in nursing infants may exist. Some sulfonylurea drugs are excreted in human milk although it is

not known whether gliclazide is one of them (See CONTRAINDICATIONS).

Pediatrics (< 18 years of age):

Safety and effectiveness of GLICLAZIDE MR in children have not been established.


Geriatrics (> 65 years of age):

Efficacy and tolerance of GLICLAZIDE MR, prescribed using the same therapeutic regimen in

subjects over 65 years, has been confirmed in clinical trials. Severe hypoglycemia can be

induced by all sulfonylurea drugs, particularly susceptible are elderly subjects.

Monitoring and Laboratory Tests

Measurement of glycated haemoglobin levels (or fasting venous plasma glucose) is

recommended in assessing blood glucose control. Blood glucose self-monitoring is also

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recommended. Blood glucose control in a patient receiving antidiabetic treatment may be

affected by fever and infection or surgical intervention. Closed monitoring is required in these

patients. In some cases, it may be necessary to administer insulin.

Hepatic function should be assessed before initiating therapy and the liver function should be

assessed periodically in patients with impaired hepatic function. In patients with impaired renal

function, blood and urine glucose should be regularly monitored. Measurements of glycated

hemoglobin levels are recommended.

Elderly patients (malnourished, with impaired hepatic, renal, or adrenal function) will require

periodic monitoring and special care.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Gliclazide modified release tablets 30 mg have been evaluated for safety in controlled clinical

trials in 955 patients, of which 728 were treated in long-term studies for up to 10 months, in

comparison with gliclazide 80 mg tablets.

The percentage of patients discontinuing treatment due to adverse events was lower in the

gliclazide modified release tablets 30 mg group (2.9%) than in the gliclazide 80 mg tablets group

(4.5%).

The most frequently reported serious adverse events during clinical trials were coronary heart

disease, cerebrovascular accidents, carcinoma, and gastrointestinal events (diarrhea, constipation,

nausea, vomiting, gastritis, flatulence, dyspepsia).

The most frequent adverse event is hypoglycemia.

Serious adverse drug reactions that resulted in hospitalization during clinical trials were malaise,

acute renal failure, and thrombophlebitis.

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Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Hypoglycemia (See WARNINGS AND PRECAUTIONS)

Severe hypoglycemia which mimics acute CNS disorders may occur. Hepatic and/or renal

disease, malnutrition, debility, advanced age, alcoholism, adrenal or pituitary insufficiency may

be predisposing factors.

In long-term studies, the percentage of patients experiencing hypoglycemic episodes was similar

between patients treated with gliclazide modified release tablets 30 mg (11.6%) and those treated

with gliclazide 80 mg tablets (11.1%). However, the number of hypoglycemic episodes for 100

patient-months was lower in the gliclazide modified release tablets 30 mg group (3.5) than in the

gliclazide 80 mg tablets group (4.8).

Analysis in elderly patients (over 65 years old) showed that this population experienced, overall,

less hypoglycemia than the whole population with a prevalence of hypoglycemic episodes lower

in the gliclazide modified release tablets 30 mg group (2.6 hypoglycemic episodes for 100

patient-months) than in the gliclazide 80 mg tablets group (4.1).

Other adverse events

Adverse events reported during controlled clinical trials with gliclazide modified release tablets

30 mg were those expected in the population of interest, a population whose underlying disease

is recognized atheromatous risk factor.

Adverse events that have been reported in at least 1.0% of diabetic patients in long-term

controlled studies, whatever their relationship to treatment, are listed by body system in the

following table. The most frequent adverse events were unspecific of the disease as respiratory

infections or back pain.

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Gliclazide Modified Release Tablets 30 mg

(n= 728) %

Gliclazide 80 mg tablets (n= 734)

%

Resistance mechanism

Infection viral 7.7 5.6

Otitis media 1.1 0.8

Respiratory

Rhinitis 4.4 4.6

Bronchitis 4.4 4.6

Pharyngitis 4.3 3.5

Upper respiratory infection 3.3 3.7

Coughing 2.1 2.0

Pneumonia 1.5 1.4

Sinusitis 1.5 1.1

Musculo-skeletal

Back pain 5.2 4.1

Arthralgia 3.0 3.5

Arthrosis 2.2 2.2

Arthritis 1.4 2.3

Tendinitis 1.1 1.0

Myalgia 2.3 1.5

Secondary term

Inflicted injury 4.3 4.5

Body as a whole

Headache 3.8 4.6

Asthenia 2.2 2.6

Cardiovascular

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Hypertension 3.2 3.7

Angina pectoris 2.1 2.2

Oedema legs 1.2 1.4

Urinary

Urinary tract infections 2.6 3.0

Gastrointestinal

Diarrhea 2.5 2.0

Constipation 1.6 1.2

Gastritis 1.2 0.5

Gastroenteritis 1.1 1.5

Nausea 1.1 0.7

Abdominal pain 1.1 1.4

Central, periph. nervous system

Dizziness 2.2 2.3

Neuralgia 1.2 0.7

Metabolism and nutrition

Hyperglycemia 1.9 2.2

Lipid metabolism disorder 1.4 0.5

Hyperlipaemia 1.0 0.8

Skin and appendages disorders

Dermatitis 1.6 1.2

Rash 1.0 1.2

Skin disorder 1.9 2.0

Pruritus 1.0 0.4

Vision disorders

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Conjunctivitis 1.0 0.8

Psychiatric disorders

Depression 1.9 1.2

Insomnia 1.1 2.0 Analysis of adverse events in sub-populations led to similar patterns as in the whole population

and showed that sex, age and renal insufficiency had no significant influence on the safety

profile of 30 mg.

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Adverse events other than those already specifically mentioned in this product monograph and

that have been reported with gliclazide modified release tablets 30 mg during long-term studies

in more than one patient and/or that have been previously reported with gliclazide 80 mg tablets

or with other sulfonylurea drugs include the following (drug relationship has not been proved for

all cases):

Body as a whole: allergy, carpal tunnel syndrome, chest pain, fever, infection, fungal infection,

leg pain, malaise, pain, weight increase.

Cardiovascular: arteritis, cardiac failure, cerebrovascular disorder, coronary artery disorder,

epistaxis, hypotension, myocardial infarction, palpitation, tachycardia, thrombophlebitis, vein

disorder.

Central, peripheral nervous system: anxiety, confusion, depression, insomnia, nervousness,

neuropathy.

Endocrine: hypothyroidism. A decrease in the uptake of radioactive iodine by the thyroid gland

has been reported with other sulfonylurea drugs. This has not been shown with gliclazide 80 mg

tablets during a study involving 15 patients.

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Gastro-intestinal: abdominal pain, anal fissure, appetite increased, colitis, duodenal ulcer,

epigastric fullness, faecal incontinence, flatulence, gastric irritation, gastroesophageal reflux, GI

neoplasm benign, hemorrhoids, melena, dry mouth, oesophagitis, saliva increased, tooth ache,

tooth disorder, vomiting. These reactions are generally dose-related and may disappear when the

dose is reduced.

Hearing and vestibular: hearing decreased, tinnitus.

Liver and biliary: increased liver enzymes, hepatitis, hepatomegaly.

Metabolic and nutritional: gout, glycosuria, hypercholesterolemia, hypertriglyceridemia, thirst.

Cases of hepatic porphyria and disulfiram-like reactions have been described with sulfonylurea

drugs. Clinical experience to date has shown that gliclazide 80 mg tablets has a low incidence of

disulfiram type reactions.

Musculo-skeletal: arthropathy, bursitis, hernia congenital, skeletal pain, spine malformation.

Reproductive: balanoposthitis, benign female breast neoplasm, impotence, mastitis, menstrual

disorder, prostatic disorder, vaginitis.

Respiratory: asthma, dyspnea, tracheitis.

Skin and appendages: fungal dermatitis, eczema, erythema, hyperkeratosis, maculopapular or

morbiliform rash, nail disorder, onychomycosis, pruritus, dry skin, skin ulceration, urticaria.

These reactions may persist during treatment, which must be then interrupted. Cases of porphyria

tarda and of photosensitivity have also been described with sulfonylurea drugs.

Urinary: albuminuria, cystitis, nocturia, polyuria, renal calculus, renal cyst.

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Vision: cataract, conjunctival haemorrhage, diplopia, glaucoma, abnormal lacrimation, retinal

disorder, abnormal vision, vitreous disorder, xerophthalmia.

Abnormal Hematologic and Clinical Chemistry Findings

The pattern of laboratory tests abnormalities previously observed with gliclazide 80 mg tablets

was similar to that for other sulfonylureas. Occasional mild to moderate elevations of hepatic

enzymes, LDH and creatinine and decrease in natremia have been observed. These

abnormalities frequently encountered with treated or untreated diabetic patients are rarely

associated with clinical symptoms and generally not considered to be drug related. As with all

hypoglycemic sulfonylurea drugs, a few rare cases of leukopenia, agranulocytosis,

thrombocytopenia and anemia have been reported with gliclazide 80 mg tablets. No laboratory

tests abnormalities other than those already reported with gliclazide 80 mg tablets have been

observed during controlled clinical trials performed on gliclazide modified release tablets 30 mg

Post-Market Adverse Drug Reactions

In post-marketing experience with gliclazide modified release tablets 30 mg, gastrointestinal

disturbance, including abdominal pain, nausea, vomiting, dyspepsia, diarrhea and constipation

have been reported. Skin and subcutaneous tissue disorders, rash, pruritus, urticaria, erythema,

maculopapular rashes and bullous reactions have been more rarely reported.

The most serious adverse drug reactions reported with gliclazide are hypoglycaemic coma,

pancytopenia, thrombocytopenia, hepatitis, cholestatic jaundice, pyrexia, pancreatitis acute and

skin reactions (pruritus and rash).

Class attribution effects: Cases of erythrocytopenia, agranulocytosis, haemolytic anaemia,

pancytopenia and allergic vasculitis, have been described for other sulphonylureas. With other

sulfonylureas cases were also observed of elevated liver enzyme levels (AST, ALT, alkaline

phosphatise) and even impairment of liver function (e.g. with cholestasis and jaundice) and

hepatitis which regressed after withdrawal of the sulfonylurea or led to life-threatening liver

failure in isolated cases. Discontinue treatment if cholestatic jaundice appears.

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DRUG INTERACTIONS

Overview

As a result of drug interaction, hypoglycemia may be potentiated when a sulfonylurea is used

concurrently with agents such as: long-acting sulfonamides, tuberculostatics, NSAIDs, fibrates,

monoamine oxidase inhibitors, salicylates, probenecid, beta-blockers, azole antifungal agents

(oral and parenteral preparations), H2 receptor antagonists and angiotensin converting enzyme

inhibitors. In addition, hypoglycemia is potentiated when gliclazide is used in combination with

other antidiabetic agents (insulin, alpha glucosidase inhibitors, biguanides) which is not

indicated.

Certain drugs tend to induce hyperglycemia and may lead to loss of blood sugar control. These

include diuretics (thiazides, furosemide), corticosteroids, oral contraceptives (estrogen plus

progestogen), chlorpromazine, ritodrine, salbutamol, terbutaline and nicotinic acid in

pharmacologic doses.

Barbiturates should be used with caution in patients receiving an oral hypoglycemic agent since

they may reduce the hypoglycemic effect.

Sulfonylureas may potentiate the action of anticoagulants. Adjustment of the anticoagulant dose

may be necessary.

Drug-Drug Interactions

Gliclazide Reference Effect Clinical comment

Miconazole (systemic route, oromucosal

gel)

C Increases the risk of

hypoglycemia

Contra-indicated combination. Increases the hypoglycaemic effect with possible onset of hypoglycaemic symptoms, or even coma.

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Phenylbutazone (systemic route)


hypoglycemia

Combination is not recommended. Increases the hypoglycaemic effect of sulphonylureas (displaces their binding to plasma proteins and/or reduces their elimination). It is preferable to use a different anti-inflammatory

agent, or else to warn the patient and emphasise the importance of self-monitoring. Where necessary, adjust the dose during and after treatment with the anti-inflammatory agent.

Other antidiabetic agents (insulins,

acarbose, biguanides)


hypoglycemia

Combinations requiring precautions for use. Potentiation of the blood glucose lowering effect and thus, in some instances, hypoglycemia may occur.

Beta-blockers C Increases the risk of

hypoglycemia


Fluconazole C Increases the risk of

hypoglycemia


Angiotensin converting enzyme

inhibitors


hypoglycemia


H2-receptor antagonists


hypoglycemia


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MAOIs C Increases the risk of

hypoglycemia


Sulfonamides C Increases the risk of

hypoglycemia


Nonsteroidal anti-inflammatory agents


hypoglycemia


Danazol C Causes an increase in

blood glucose levels

Combination is not recommended because of diabetogenic effect of danazol. If the use of this active substance cannot be avoided, warn the patient and emphasise the importance of urine and blood glucose monitoring. It may be necessary to adjust the dose of the antidiabetic agent during and after treatment with danazol.

Chlorpromazine (neuroleptic agent)

C Causes an increase in


Combination requiring precautions during use. High doses (>100 mg per day of chlorpromazine) increase blood glucose levels (reduced insulin release). Warn the patient and emphasise the importance of blood glucose monitoring. It may be necessary to adjust the dose of the antidiabetic active substance during and after treatment with the neuroleptic agent.

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Glucocorticoids (systemic and local

route: intra-articular, cutaneous and rectal

preparations) and tetracosactrin



Combination requiring precautions during use. Increase in blood glucose levels with possible ketosis (reduced tolerance to carbohydrates due to glucocorticoids). Warn the patient and emphasise the importance of blood glucose monitoring, particularly at the start of treatment. It may be necessary to adjust the dose of the antidiabetic active substance during and after treatment with glucocorticoids.

Ritodrine, salbutamol,

terbutaline: (I.V.)



Combination requiring precautions during use. Increased blood glucose levels due to beta-2 agonist effects. Emphasise the importance of monitoring blood glucose levels. If necessary, switch to insulin.

Anticoagulant therapy (Warfarin

and other)

C Potentiation of

anticoagulation

Combination which must be taken into account. Sulfonylureas may lead to potentiation of anticoagulation during concurrent treatment. Adjustment of the anticoagulant may be necessary.

Drugs containing alcohol


hypoglycemia

Intolerance to alcohol (disulfiram-like reaction: flushing, sensation of warmth, giddiness, nausea and occasionally tachycardia) may occur in patients treated with sulfonylurea.

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

Drug-Food Interactions

There are no established drug-food interactions.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

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Drug-Lifestyle Interactions

This treatment should only be prescribed if the patient is likely to have a regular food intake

(including breakfast). It is important to have a regular carbohydrate intake due to the increased

risk of hypoglycemia if a meal is taken late, if an inadequate amount of food is consumed or if

the food is low in carbohydrate. Hypoglycemia is more likely to occur during periods of low-

calorie diet and following prolonged or strenuous exercise. Intolerance to alcohol (disulfiram-

like reaction: flushing, sensation of warmth, giddiness, nausea and occasionally tachycardia) may

occur in patients treated with sulfonylurea. Alcohol increases the hypoglycaemic reaction (by

inhibiting compensatory reactions) that can lead to the onset of hypoglycaemic coma. Avoid

alcohol or medicines containing alcohol.

Treatment with GLICLAZIDE MR can have effects on ability to drive and use machines.

Patients should be made aware of the symptoms of hypoglycemia and should be careful if

driving or operating machinery, especially at the beginning of treatment.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Determination of the proper dosage for GLICLAZIDE MR for each patient should be made on

the basis of frequent determinations of blood glucose during dose titration and throughout

maintenance.

The daily dose of GLICLAZIDE MR may vary from 30 to 120 mg (1 to 4 tablets) once daily.

Recommended Dose and Dosage Adjustment

The recommended starting dose of GLICLAZIDE MR is 1 tablet per day (30 mg), even in

elderly patients (over 65 years old).

A single daily dose provides effective blood glucose control. The single daily dose may be

between one and three, or even four, tablets. The daily dose should not exceed 120 mg.

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Dose adjustment should be carried out in steps of 30 mg, according to the blood glucose

response. Each step should last for at least two weeks.

Administration

It is recommended that the medication be taken at breakfast time. The tablets should be

swallowed whole and must not be chewed or crushed.

– Previously untreated patients should commence with a dose of 30 mg and will benefit

from dose adjustment until the appropriate dose is reached.

– GLICLAZIDE MR can replace gliclazide 80 mg immediate release tablets.

– GLICLAZIDE MR can replace an antidiabetic treatment without any transitional period.

If a patient is switched from a hypoglycemic sulfonylurea with a prolonged half-life (i.e.

chlorpropamide) he/she should be carefully monitored (for 1 to 2 weeks) in order to avoid

hypoglycemia due to possible residual effects of the previous therapy.

It is advisable to ascertain the contribution of the drug in control of the blood glucose level by

discontinuing the medication semi-annually or at least annually with careful monitoring of the

patient. If the need for the drug is not evident, the drug should not be resumed. In some diabetic

subjects, short-term administration periods of the drug may be sufficient during periods of

transient loss of blood sugar controls.

Geriatrics

The efficacy and tolerance of gliclazide modified-release tablets 30 mg, prescribed using the

same therapeutic regimen in subjects over 65 years, has been confirmed in clinical trials. The

dosage will therefore be identical to that recommended for adults under the age of 65 years.

Renal Insufficiency

The efficacy and tolerance of gliclazide modified-release tablets 30 mg, prescribed using the

same therapeutic regimen in subjects with mild to moderate renal failure (creatinine clearance of

between 15 and 80 mL/min), has been confirmed in clinical trials. The dosage will therefore be

identical to that in subjects with normal renal function.

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Patients receiving Insulin

Maturity onset diabetics with no ketoacidosis or history of metabolic decompensation and whose

insulin requirements are less than 40 units per day may be considered for GLICLAZIDE MR

therapy after cessation of insulin.

If a change from insulin to GLICLAZIDE MR is contemplated in such a patient, discontinue

insulin for a period of 2 or 3 days to determine whether any therapy other than dietary regulation

and exercise is needed. During this insulin-free interval, test the patient's urine at least 3 times

daily for glucose and ketone bodies and monitor the results carefully. The appearance of

significant ketonuria accompanied by glucosuria within 12 to 24 hours after the withdrawal of

insulin, strongly suggests that the patient is ketosis prone, and precludes the change from insulin

to sulfonylurea therapy.

Missed Dose

If a dose is forgotten, the dose taken on the next day should not be increased.

OVERDOSAGE

Symptoms

Overdosage with sulfonylureas may result in hypoglycemia but it should be noted that the dosage

which causes such hypoglycemia varies widely and may be within the accepted therapeutic range

in sensitive individuals.

The manifestations of hypoglycemia include sweating, flushing or pallor, numbness, chilliness,

hunger, trembling, headache, dizziness, increased pulse rate, palpitations, increased blood

pressure and apprehensiveness in mild cases. In more severe cases, coma appears.

However, symptoms of hypoglycemia are not necessarily as typical as those described above and

sulfonylureas may cause insidious development of symptoms mimicking cerebrovascular

insufficiency.

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Treatment of Overdosage

Discontinue medication and treat hypoglycemia by giving dextrose promptly and in sufficient

quantity. Some sulfonylurea-induced hypoglycemias may be refractory to treatment and

susceptible to relapse especially in elderly or malnourished patients. Continuous dextrose

infusions for hours or days have been necessary. Strict monitoring should be continued until the

doctor is sure that the patient is out of danger.

Severe hypoglycaemic reactions, with coma, convulsions or other neurological disorders are

possible and must be treated as a medical emergency, requiring immediate hospitalisation. If

hypoglycaemic coma is diagnosed or suspected, the patient should be given a rapid I.V. injection

of 50 mL of concentrated glucose solution (20 to 30%). This should be followed by continuous

infusion of a more dilute glucose solution (10 %) at a rate that will maintain blood glucose levels

above 1 g/L. Patients should be monitored closely and, depending on the patient's condition after

this time, the doctor will decide if further monitoring is necessary. Dialysis is of no benefit to

patients due to the strong binding of gliclazide to proteins. For management of a suspected

overdose, contact your Regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

GLICLAZIDE MR (gliclazide) is a hypoglycemic agent of the sulfonylurea group. The

hypoglycemic action of GLICLAZIDE MR is related to an improvement in insulin secretion

from the functioning beta cells of the pancreas. It potentiates the insulin release, improves the

dynamics of insulin. Increase in postprandial insulin and C-peptide secretion persists after two

years of treatment. Gliclazide has extra-pancreatic actions. These metabolic actions are

accompanied by hemovascular effects. However, the mechanism of action regarding these

effects is still poorly understood. The clinical significance of these effects has not been

established.

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Effects on insulin release. In type 2 diabetics, gliclazide restores the first peak of insulin

secretion in response to glucose and increases the second phase of insulin secretion. A significant

increase in insulin response is seen in response to stimulation induced by a meal or glucose.

Extra-pancreatic effects. It has been demonstrated that gliclazide increases peripheral insulin

sensitivity:

– In muscle: the action of insulin on glucose uptake, measured during an euglycemic

hyperinsulinemic clamp is significantly increased (+35%), due to an improvement in

peripheral sensitivity to insulin. This leads to an improvement in diabetes control. Gliclazide

acts mainly by potentiating insulin action on muscle glycogen synthetase. Moreover, results

of studies on the muscle are consistent with a post-transcriptional action of gliclazide on

GLUT4 glucose carriers;

– In the liver: studies on glucose turnover show that gliclazide decreases hepatic glucose

production, leading to an improvement in fasting blood glucose levels.

Hemovascular effects. Gliclazide decreases microthrombosis by two mechanisms which may be

involved in complications of diabetes:

– A partial inhibition of platelet aggregation and adhesion, with a decrease in the markers of

platelet activation (beta thromboglobulin, thromboxane B2):

– A restoration of the vascular endothelium fibrinolytic activity with an increase in t-PA

activity.

Antioxidant effects. A controlled clinical study in diabetics has confirmed the antioxidant effects

of gliclazide that were already demonstrated in clinical pharmacology: reduction in plasma levels

of lipid peroxides, increase in the activity of erythrocyte superoxide dismutase.

Pharmacodynamics

Hypoglycemic activity

The main mechanism of action of gliclazide consists in an increase in the insulin secretory

potential of pancreatic beta-cells in a situation of hyperglycemia. This effect of gliclazide on

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insulin secretion is maintained during long-term treatment in type 2 diabetic patients. It was

observed that the administration of gliclazide was followed by:

– a consistent and significant decrease in fasting blood glucose;

– a more than 1% decrease in mean glycated hemoglobin;

– an inhibition by 12 to 27% of the rise in blood glucose after a standard meal or an oral glucose

load.

A slight and transitory increase in mean fasting plasma insulin levels was occasionally observed

with gliclazide treatment.

Regarding the biphasic nature of insulin secretion, the first peak, that is severely blunted in type

2 diabetes, is improved during gliclazide treatment.

In addition to the effect of gliclazide on the secretion of insulin, extrapancreatic effects have also

been evidenced. Gliclazide improves peripheral sensitivity to insulin and increases glucose

utilization rate:

– with euglycemic hyperinsulinemic clamps in obese and non-obese type 2 diabetic patients, it

has been shown that gliclazide, after 3 months of treatment, increases the disappearance rate

and metabolic clearance of glucose at the highest insulin infusion rates (100 and 300

mU/kg/h);

– in comparison to diet treatment, gliclazide also enhances insulin-stimulated glucose

metabolism after 8 weeks of treatment by potentiating insulin action on skeletal muscle

glycogen synthetase.

Studies on glucose turnover have also shown that basal hepatic glucose production, measured by

tracer methodology, was markedly reduced (28-50%) after 3 months of treatment.

Hemovascular activity

Gliclazide possesses anti-platelet properties which are independent of its antidiabetic action, and

improves the fibrinolytic potential in diabetic patients:

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– numerous studies have shown inhibitory effects of gliclazide on platelet aggregation and

hyperadhesiveness.

A statistically significant 22% decrease in collagen-induced platelet aggregation has been

observed after 3 and 6 months of treatment with gliclazide in 15 patients previously well

controlled under glibenclamide. A concentration-dependent inhibition of PAF-induced

platelet aggregation has also been reported with gliclazide in vitro in platelet-rich plasma

from healthy subjects and type 2 diabetic patients. Finally, a consistent decrease in markers

of platelet activation (e.g. beta thromboglobuline and thromboxane B2 levels) has been

observed with gliclazide whether glycemic control improved or not; change to gliclazide of

patients treated since several years by chlorpropamide is followed by normalisation of the t-

PA activity, sustained over 24-48 months. This has been confirmed by 2 studies in type 1 and

glibenclamide treated type 2 diabetics: in both, the addition of gliclazide to insulin or the

switch to this sulfonylurea were followed by significant increase in t-PA and in the activity

of the intrinsic fibrinolytic system.

Antioxidant activity

Gliclazide is a strong free radical scavenging agent, an effect demonstrated both in vitro and in

patient. In 17 type 2 diabetic patients switched to gliclazide and seen at regular intervals during a

36-week period, peroxidized lipids and oxidized damaged IgG decreased significantly. These

effects of gliclazide on the oxidative stress have been confirmed in a double-blind study in

diabetic patients. Highly significant and sustained decrease in peroxidized lipid levels and

increase in erythrocyte superoxide dismutase activity were obtained with gliclazide, but not with

glibenclamide.

Pharmacokinetics The initial development of gliclazide led to the marketing of two different formulations of 80 mg

tablets worldwide, with only one formulation being registered in each country. Although the two

formulations differed substantially in their pharmacokinetic performance in vivo, there was no

evidence that they were different in their efficiency and safety in type 2 diabetic patients, thus

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suggesting that gliclazide does not exert its effect in a dose-dependent manner but by virtue of a

threshold plasma drug concentration. Both formulations of gliclazide are prescribed in the dose

range 80-320 mg per day, tablets being taken once to 3-times daily. Individual dose requirements

vary between patients, which most likely reflect the inter-individual variability in

pharmacokinetic characteristics in addition to differences in diabetes severity. Also the noted

variability in prescribed average dose between countries may partly be explained by differences

in the marketed pharmaceutical formulation. It was therefore essential to develop a new

standardized pharmaceutical formulation for worldwide use, presenting optimal and consistent

release characteristics. Furthermore, it was thought that a medication suitable for once-daily

administration would be desirable. These considerations led to the development of a new

modified release formulation of gliclazide.

Gliclazide is slowly and completely absorbed from the gastro-intestinal tract and plasma levels

increase progressively, resulting in a plateau-shaped curve from the sixth to the twelfth hour after

administration of gliclazide modified release tablets 30 mg. Intra-individual variability is low.

Food intake does not affect the rate and extent of absorption. The relationship between the dose

administered and the area under the concentration curve as a function of time is linear. In man it

is highly bound to plasma proteins, about 95 %. The mean elimination half life in man

approximates 16 hours. A single daily dose of gliclazide modified release tablets 30 mg

maintains effective gliclazide plasma concentrations over 24 hours. No clinically significant

modifications in the pharmacokinetic parameters have been observed in elderly patients.

Following oral administration the unchanged gliclazide in plasma is extensively metabolized

with little of the unchanged compound (< 1%) appearing in the urine. No active metabolites have

been detected in plasma. Gliclazide metabolites and conjugates are primarily eliminated via

kidneys 60 to 70%, and about 10 to 20% via feces. Six principal metabolites have been identified

in urine, essentially oxidized and hydroxylated derivatives, and two glucuronoconjugates.

Absorption:

The absorption of gliclazide from gliclazide modified release tablets 30 mg is slow and complete

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(mean absolute bioavailability of 97%) and is not affected by simultaneous food intake. Plasma

concentrations rise gradually and the maximum concentration is usually reached after about 6

hours, with a plateau maintained for another 4 to 6 hours.

Distribution:

The volume of distribution is relatively small which can partially be explained by high protein

binding (about 95 %).

Metabolism:

Although more than 90% of unchanged gliclazide is found in plasma following administration,

this is intensively metabolized with little of the unchanged compound (<1%) found in urine. Six

principal metabolites have been found in urine, essentially oxidized and hydroxylated

derivatives, and two glucuronoconjugates. No active metabolites have been detected in plasma.

The principal metabolic pathways of gliclazide may be summarized as shown hereafter.

Excretion:

Gliclazide is essentially eliminated via the urine: 60 to 70% as against 10 to 20% via feces.

The mean elimination half life is 16 h (range 12-20 h). Linear kinetics were observed with

gliclazide modified release tablets 30 mg in the dose range up to 90 mg.

Special Populations and Conditions

Pediatrics:

Safety and effectiveness of GLICLAZIDE MR in children have not been established.


Gender:

No significant relationship was found between any of the pharmacokinetic parameters and the

covariables gender, body weight and creatinine clearance.

STORAGE AND STABILITY

Store at room temperature (15°C - 25°C). Protect from humidity.

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DOSAGE FORMS, COMPOSITION AND PACKAGING Dosage form:

GLICLAZIDE MR (gliclazide modified release tablets) 30 mg: White, to off-white, flat-faced,

bevelled edge, capsule shaped tablets, engraved “30” on one side and plain on the other side.

Composition: Each tablet (90 mg) contains: active principle: 30 mg gliclazide excipients: colloidal silicon dioxide

hydroxypropyl methylcellulose stearic acid

Packaging:

GLICLAZIDE MR is available in bottles of 100.

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PART II: SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION Drug Substance Proper name: Gliclazide Chemical name: 1-(3-Azabicyclo [3.3.0]-oct-3-yl)-3-(p-tolylsulfonyl) urea Molecular formula: C15H21N3O3S Molecular mass: 323.42 Structural formula:

Physicochemical properties: Physical form: white, crystalline powder

Solubility: Practically insoluble in water; freely soluble in

dichloromethane; sparingly soluble in acetone.

pKa: 5.8

Partition Coefficient: pH % gliclazide in organic phase

(water/CHCl3)

0 to 7 almost 100%

8.6 80%

9.0 55%

10.0 12%

Melting Point: Approximately 168°C

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CLINICAL TRIALS Two pivotal controlled clinical studies involving a total of 888 type 2 diabetic patients have been

conducted during the development of the modified release (MR) formulation of gliclazide.

The first study was a phase II, multicentre, comparative, randomized, double-blind trial designed

to evaluate the dose/efficacy relationship of the MR formulation administered once daily and to

determine its minimum effective dose. Placebo and five gliclazide MR doses (15, 30, 60, 90 and

135 mg) were assessed over 8 weeks in 224 patients (35 to 39 patients per group). The lowest

tested dose (15 mg once daily) slightly decreased fasting plasma glucose (FPG) but the effect of

this dose on glycated hemoglobin (HbA1c) was not clinically significant. The first gliclazide MR

dose demonstrating clinically relevant efficacy on both parameters was 30 mg once daily. For

doses above 30 mg, the efficacy of the gliclazide MR formulation was confirmed with a good

clinical and biological acceptability. This study thus demonstrated that 30 mg of gliclazide MR

administered once daily is the minimum effective dose for initiating treatment in type 2 diabetic

patients.

The second study was a large phase III, multinational, comparative, randomized, double-blind

trial aimed at demonstrating the therapeutic equivalence of gliclazide MR compared to the

gliclazide 80 mg conventional formulation marketed in Canada. A total of 664 patients were

randomized in two parallel groups, one assigned to gliclazide 80 mg (336 patients) and one to

gliclazide MR (328 patients). After a 4-month dose escalating period allowing patient-tailored

titration, patients entered a maintenance period of 6 months. Gliclazide 80 mg was administered

at 80, 160, 240 or 320 mg/day, with doses above 80 mg given twice daily; gliclazide MR was

always administered once daily at breakfast time at 30, 60, 90 or 120 mg/day. The study

demonstrated that after 10 months of treatment, gliclazide MR is at least as effective as gliclazide

80 mg in controlling HbA1c and FPG levels of type 2 diabetic patients. The therapeutic

equivalence was actually achieved with lower daily doses of the MR formulation, 30 mg of

gliclazide MR producing a similar effect as 80 mg of gliclazide conventional formulation. The

general safety of both formulations was good with no difference in type and incidence of adverse

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events. With regard to hypoglycemia, the number of patients experiencing hypoglycemic

episodes was almost the same in both groups. However, the number of hypoglycemic episodes

was lower in the gliclazide MR group than in the gliclazide 80 mg group.

Comparative Bioavailability Studies

Comparative bioavailability studies were conducted under fasting and fed conditions, using

GLICLAZIDE MR, and the reference product, Diamicron® MR (manufactured by Servier

Canada Inc.). The study consisted of a randomized, single dose (1 x 30 mg gliclazide), crossover

design, with two treatments and two periods. Nineteen (19) healthy male/ female volunteers

completed each study in its entirety.

Summary Table of the Comparative Bioavailability Data Gliclazide

(A single 30 mg dose: 1 x 30 mg) From Measured Data/Fasting Conditions

Geometric Least Square Mean Arithmetic Mean (CV%)

Parameter Gliclazide MR Diamicron® MR† Ratio of Geometric Means (%)##

90% Confidence

Interval (%)##

AUCt (ng•h/mL)

17742.5

18962.0 (42)

16957.3

18200.9 (44)

104.6 99.8 – 109.7

AUCinf (ng•h/mL)

18910.2

20810.1 (54)

18135.2

20092.3 (58)

104.3 99.7 – 109.1

Cmax (ng/mL)

643.2

667.6 (28)

718.2

738.9 (21)

89.6 83.1 – 96.5

Tmax# (h) 12.74 (43) 9.06 (26)

Thalf# (h) 15.68 (37) 16.60 (38) # Arithmetic means (CV%) only. ## Based on the least squares estimate. † Diamicron® MR is manufactured by Servier Canada Inc., and was purchased in Canada.

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Summary Table of the Comparative Bioavailability Data

Gliclazide (A single 30 mg dose: 1 x 30 mg)

From Measured Data/Fed Conditions Geometric Least Square Mean

Arithmetic Mean (CV%) Parameter Gliclazide MR Diamicron® MR† Ratio of Geometric

Means (%)## 90%

Confidence Interval (%)##

AUCt (ng•h/mL)

16072.1

16643.3 (27)

16165.9

16718.9 (28)

99.4 95.4 – 103.6

AUCinf (ng•h/mL)

16860.1

17626.2 (33)

17140.0

18154.4 (42)

98.4 93.9 – 103.1

Cmax (ng/mL)

853.5

876.2 (23)

962.6

987.3 (21)

88.7 80.6 – 97.6

Tmax# (h) 6.43 (24) 6.11 (37)

Thalf# (h) 14.51 (31) 15.37 (49) # Arithmetic means (CV%) only. ## Based on the least squares estimate. † Diamicron® MR is manufactured by Servier Canada Inc., and was purchased in Canada.

A comparative bioavailability study was conducted under fasting steady-state conditions, using

GLICLAZIDE MR, and the reference product, Diamicron® MR (manufactured by Servier

Canada Inc.). The study consisted of a randomized, single dose (1 x 30 mg gliclazide at time zero

(0) and every 24 hours thereafter for the next 5 days [24, 48, 72, 96 and 120 hours] for each

period of the study), crossover design, with two treatments and two periods. Eighteen (18)

healthy male/ female volunteers completed this study in its entirety.

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Summary Table of the Comparative Bioavailability Data

Gliclazide (Multiple dose: 1 x 30 mg)

From Measured Data/Steady State Geometric Mean##

Arithmetic Mean (CV%) Parameter Gliclazide MR Diamicron® MR† Ratio of Geometric

Means (%)## 90%

Confidence Interval (%)##

AUCtau (ng•h/mL)

19093.4

19935.8 (33)

18855.0

19329.8 (24)

101.3 94.3 – 108.7

Cmax (ng/mL) 1067.1

1107.5 (30)

1138.4

1162.5 (22)

93.7 86.0 – 102.2

Cmin (ng•h/mL) 456.5

509.0 (49)

471.9

497.9 (36)

96.7 83.2 – 112.4

Tmax# (h) 7.71 (47) 7.65 (32)

Fluc# (%) 75.6 (26) 84.7 (19) # Arithmetic means (CV%) only. ## Based on the least squares estimate. † Diamicron® MR is manufactured by Servier Canada Inc., and was purchased in Canada.

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DETAILED PHARMACOLOGY

ANIMAL PHARMACOLOGY

Pharmacokinetics and Metabolism

This has been studied in four animal species (monkey, dog, rabbit and rat) after single or

repeated oral administration of gliclazide. The principal characteristics are shown in the table

below.

BLOOD KINETICS OF GLICLAZIDE (PO) IN DIFFERENT SPECIES (single doses) Species

Number of

subjects (doses)

Absorption

T2 (h)

Plasma peak (h)

Volume of

distribution (% body weight)

Plasma half-

time (h)

Monkey

4

3 and 50 mg/kg

0.3 1

1-2 1

24.4 1

108 4

2.9 1

6.2 4

Beagle

3

3 and 50 mg/kg

0.7 1

2-6 1

21.3 1

22 4

10.7 1

9.9 4

Rabbit

5

10 and 25 mg/kg

0.7 2

3 2

30.8 2

51.8 3

3.9 2

5.9 3

Rat

5

10 mg/kg

0.5 2

1 2

53.8 2

-

2.5 2

-

1 = 3 mg/kg PO 3 = 25 mg/kg PO 2 = 10 mg/kg PO 4 = 50 mg/kg PO Gliclazide is rapidly absorbed in all species, with a plasma peak observed between 1 and 6 hours.

More than 90% of gliclazide is found unchanged in the plasma. Elimination from plasma is

monophasic with inter-species variations concerning half-life.

Excretion is similar in all species with 60 to 70% of the dose found in urine and 10 to 20% in

feces.

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The drug is extensively metabolized into at least 5 metabolites and only small amounts of

unchanged compound are excreted in the urine.

Hypoglycemic activity

The hypoglycemic action of gliclazide has been observed in the rat, rabbit, guinea-pig and dog

following intravenous or oral administration. The degree and duration of these effects are dose

dependent.

Comparison of ED 30 shows that gliclazide is 9 times more active than tolbutamide in the rabbit

and 25 times more active in the rat. The duration of action of gliclazide is also greater than that

of tolbutamide.

Gliclazide stimulates the insulin secretion and particularly restores the early peak in the isolated

perfused pancreas of diabetic rats.

This insulinotropic action is related to the transfer of calcium into the pancreatic cell. Gliclazide

is not involved in the biosynthesis of insulin induced by glucose but modifies the distribution of

calcium in isolated rat pancreas cells.

At the extrapancreatic level, gliclazide potentialises the action of insulin on the glucose

intracellular transfer and influences its oxidation on an isolated adipocyte model when insulin is

present in the medium.

Hemovascular activity

Gliclazide delays the development of the mural thrombus formed after electrical lesion of the

vascular endothelium in the rat and increases its disaggregation speed.

In dog, gliclazide prevents the formation of capillary ADP-induced platelet aggregates at the

retinal level.

These properties can be explained by its action on:

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– the platelet behavior: reduction of the platelet adhesiveness in the diabetic rabbit and of

platelet aggregation induced by ADP or by collagen in the rabbit;

– the prostaglandin equilibrium: inhibition of the acid arachidonic release and in vitro

thromboxan synthesis and increase in the PGI2 production;

– the parietal fibrinolysis: increase in the release of the parietal plasminogen activator (t-PA).

This activator of endothelial origin, acts on plasmin which is the enzyme degrading fibrin.

Gliclazide improves vascular function in diabetic animals by preventing the abnormal

contracting effect of acetylcholine after NO synthesis inhibition. Protective properties of

gliclazide on capillary permeability have also been demonstrated in the cheek pouch model in

streptozotocin-diabetic Syrian hamsters.

Long-term treatment of diabetic sand rats with gliclazide prevents development of arterial

lesions.

Other actions

Gliclazide has no action on the central nervous system, autonomic nervous system nor

respiratory, gastro-intestinal systems.

Treatment of streptozotocin-diabetic rats with gliclazide has shown a significant improvement in

heart function.

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TOXICOLOGY

Acute toxicity

Species

Mean Weight

Number of animals

per lot

LD50

(mg/kg) Mouse CD-SPF

25 g

10 M 10 F

> 3000

Mouse ICR-HAN

20 g

10 M 10 F

> 4000

10 M

3733

5200 2679

Rat SD-SPF

250 g 10 F

3407

5467 2123

Rat CFY

110 g

6 M 6 F

> 4000

48 hours

10 days

4 M

1732

1999 1501

1599

2016 1269

Tricolour Guinea Pig

240 g

4 F

2244

2509 1944

2068

2553 1675

Beagle Dog

7 kg

3 M 3 F

> 3000

The LD50 is greater than 3000 mg/kg in the mouse, rat and dog (i.e. 300 times the therapeutic

dose) and than 2000 mg/kg in the guinea-pig (i.e. 500 times the therapeutic dose).

Symptomatology is essentially linked to the hypoglycemic effect of the drug.

Sub-chronic Toxicity

– Maximum tolerated dose:

In the dog, this dose is between 150 and 200 mg/kg by daily administration.

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– Four-week oral toxicity study in the Beagle dog:

Groups of 4 Beagle dogs (2 males, 2 females), were treated for 30 days with 0, 15, 30, 45 or

90 mg/kg/day. At the dose of 90 mg/kg, 2 animals died as a result of prolonged hypoglycemic

coma following 2 weeks of treatment. All others showed normal behaviour, with the

exception of an increase in the weight of the liver. No evidence was found of any change in

biochemical (apart from the fall in blood glucose), hematological and histopathological

parameters.

– Two-month oral toxicity study in the guinea-pig:

Groups of 10 guinea-pigs (5 males, 5 females), were treated 6 days out of 7 for 2 months with

0, 25, 50 or 100 mg/kg/day. Only male animals in the 50 mg/kg group showed delayed weight

gain. All others had normal biochemical, hematological and histopathological results.

Chronic Toxicity

– Six-month study in the Sprague-Dawley rat:

Groups of 20 rats (10 males, 10 females) weighing 300 g, were treated for 6 days out of 7 for

6 months with 0, 25, 100 or 200 mg/kg/day. Seven deaths occurred as a result of technical

problems. All other animals showed normal behaviour and haematological results. From a

biochemical standpoint, blood urea decreased significantly in the male rats as did blood

glucose in the males of the 100 mg/kg/day group. Histological examination showed an

increase in the weight of the liver and kidneys in male animals, not accompanied by any

histological lesion.

A six-month rat study carried out in Japan with higher doses (50, 100, 200, 400 and 800

mg/kg) indicates a possible higher sensibility in the female to the product: slight increases in

liver enzymes together with slight decreases in erythrocytes counts, hematocrit values and

hemoglobin concentrations at doses of 200 mg/kg and higher.

– Six-month study in the Beagle Dog

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Groups of 6 dogs (3 males, 3 females) were treated daily for 6 months with 15 or 30 mg/kg of

gliclazide or 50 mg/kg of tolbutamide.

From a clinical standpoint:

• 3 deaths (one at 15 mg/Kg, two at 30 mg/Kg) in the gliclazide group as a result of

hypoglycemic coma;

• 1 convulsion, 4 cases of severe gastro-intestinal disturbances in the tolbutamide group;

• Weight changes and food consumption were similar with both drugs.

From a laboratory standpoint:

• 40% fall in blood glucose in animals treated with gliclazide.

• Signs of hepatotoxicity in the tolbutamide group.

From a histological standpoint:

• Increase in weight of the liver in the 3 deaths of the gliclazide group.

• Increase in the weight of the liver and lesions of toxic hepatitis in 5 animals out of 6 of

the tolbutamide group.

– Twelve-month oral toxicity study in the Beagle Dog

Groups of 8 dogs (4 males, 4 females) were treated for 12 months with 0, 12 or 24 mg/kg/day

of gliclazide. Four animals in each group were sacrificed after 90 days.

• there were no deaths;

• no evidence of any modification in behaviour and body weight;

• significant fall in blood glucose;

• fluctuation in certain parameters (liver enzymes, lipid profile, creatinine);

• at autopsy: swelling of the renal and hepatic parenchyma and at the highest dose a slight

increase in the weight of the thyroid and slight decrease in the weight of the pituitary

gland.

– Twelve-Month Oral Toxicity Study in the Rhesus Monkey

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Groups of 8 rhesus monkeys (4 males, 4 females) were treated daily for 12 months with 0,

20, 60 or 180 mg/kg of gliclazide.

• no evidence was found of any modification in weight gain nor food consumption;

• significant fall in blood glucose;

• irregular rise in some liver enzymes in some animals;

• no abnormality by histopathological examination.

Teratogenicity

Teratogenicity studies have been carried out in three species: mouse, rat and rabbit.

– In the CD/SPF mouse (group of 30 females), administration of gliclazide at doses of 0, 50,

200 and 500 mg/kg/day starting from mating and throughout gestation did not modify

fertilization and abortion rates and had no apparent teratogenic effect.

– In the CFY-SPF rat (groups of 20 females), administration of gliclazide at doses of 0, 50, 100

and 200 mg/kg/day from the 6th to the 15th day of gestation did not show any embryotoxic

effect.

– In the SD/SPF rat (groups of 60 females), administration of gliclazide at the doses of 0, 15,

30, 60, 120, 240 and 480 mg/kg/day throughout gestation had no effect on fertilization,

gestation, mean number of fetuses or incidence of fetal abnormalities. The number of

offspring surviving at 48 hours was decreased in the 15, 60, 120 and 480 mg/Kg groups. No

other abnormality was seen.

– In the common rabbit (group of 15 females), administration of gliclazide at doses of 0, 10, 25

and 50 mg/kg/day from the 6th to the 18th day of gestation had no effect on the number of

fetal resorptions, percentage of abortion nor the mean number of fetuses per litter.

– In the New Zealand rabbit (group of 6 females), administration of gliclazide at doses of 0, 50,

75, 100 and 200 mg/Kg/day for 13 days followed by an observation period of 8 days, was

associated with maternotoxicity and embryotoxicity in the form of gastro-intestinal and renal

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lesions accompanied by anorexia and weight loss. However, there was no evidence of any

teratogenic effect.

Fertility and reproduction

– In the SD rat, groups of 40 females and of 20 males were treated for 8 and 70 days

respectively, before mating and until weaning in the females, and until 15 days after littering

in the males, with gliclazide at doses of 0, 10, 50 and 200 mg/Kg/day.

There was no evidence of any change in fertilization nor abortion rates. Fetal resorption,

placental hemorrhage and fetal atrophy rates were unaffected. The genital tract of treated

parents showed no abnormality imputable to treatment. No embryotoxic effect was seen on

fetuses of females sacrificed before littering. In females in which gestation was allowed to

run to term, a significant decrease in the viability of offspring was seen at 48 hours. No

abnormality was seen during the study of fertility and reproduction in first generation

offspring born of treated animals.

Mutagenicity of gliclazide

The mutagenic potential of gliclazide has been sought using six mutagenesis tests, i.e.:

– 2 gene mutation tests (Ames test);

– 1 in vitro chromosomal aberration test (human lymphocyte test);

– 2 in vivo chromosomal tests (micronucleus test);

– 1 unscheduled DNA synthesis test.

Gene mutation tests

Ames Test

1st test

In this test, gliclazide was used in the presence of 5 strains of Salmonella typhimurium (TA

1535/1537/1538/98/100) at the doses of 0, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 3, 5 and 8 mg/petri dish,

with and without metabolic activators. Positive controls were used for each strain with and

without metabolic activators. The qualitative test showed no mutagenic effect. The quantitative

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test at doses of 0.005 mg to 8 mg/dish showed no significant increase in the number of

revertants.

Thus no mutagenic effect was seen under the experimental conditions adopted.

2nd test

This test used 7 strains of Salmonella typhimurium (TA 97/98/100/102/ 1535/1537/1538) at the

doses of 0, 0.05, 0.1, 0.5, 1, 3, 5 and 8 mg of gliclazide per petri dish, in the presence and

absence of metabolic activator. Positive controls were used for each strain, with and without

metabolic activators.

No mutagenic effect was seen in the qualitative test. No mutagenic activity was detected in the

quantitative test under the experimental conditions described.

In vitro chromosomal aberration test

Possible clastogenic potential action of gliclazide on activated lymphocytes in culture was

studied by the human lymphocyte test with and without metabolic activators. Maximum

tolerated doses determined in the preliminary toxicity test were 0.033 mg/ml with metabolic

activators and 0.1 mg/ml without metabolic activator.

Gliclazide was used at the following concentrations:

– 0, 0.003, 0.01 and 0.033 mg/ml with metabolic activators;

– 0, 0.01, 0.033 and 0.1 mg/ml without metabolic activator.

Cyclophosphamide (0.02 mg/ml) and bleomycin (0.250 mg/ml) were used as positive controls

with and without metabolic activators. Gliclazide was not found to have any clastogenic activity

under the experimental conditions described.

In vivo chromosomal aberration

Micronucleus Test:

1st Test

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The test used three groups of 10 OF1 mice: 1 negative control, 1 gliclazide high dose (2 g/kg x

2), 1 gliclazide low dose (1 g/kg x 2) and one group of 5 positive control mice given

cyclophosphamide (50 mg/kg x 2). No evidence was found of any significant variation in the

number of erythrocyte micronuclei. Gliclazide was not associated with any mutagenic action

detectable by the micronucleus test.

2nd test

The test used SPF Swiss mice as follows:

– 24 mice for the preliminary toxicology test which determined the maximum administrable

dose as 3 g/kg;

– 108 mice in the phase 1 genetic toxicology test with study of effect/time relationship at the

maximum administrable dose (MAD) (sacrifice of animals at times 24, 48 and 72 hours);

– 60 mice in the phase 2 genetic toxicology test with study of the dose/effect relationship at the

time defined in phase 1 (t = 24 h) and using the following doses: 0, 750 (MAD/4), 1500

(MAD/2) and 3000 mg/Kg (MAD).

Cyclophosphamide 50 mg/kg was used as positive control. Gliclazide was found to be free of

any clastogenic activity under the experimental conditions adopted in this trial involving oral

administration in the Swiss mouse.

Unscheduled DNA synthesis

The potential of gliclazide to induce unscheduled DNA synthesis in the liver of orally dosed

male Wistar rats was investigated using an in vivo/in vitro procedure. Doses of 0, 632.5 and

2000 mg/kg of gliclazide were administered by gavage. Two samples were planned and collected

approximately 12-14 h or 2-4 h after dosing. Primary cultures of hepatocytes were prepared from

3 animals per dose. In vitro, the aim was to determine the net grain count. Plasma levels of

gliclazide were measured 2 hours after dosing with 2000 mg/kg. Under the conditions of this

study, gliclazide did not induce unscheduled DNA synthesis in rats properly exposed to the drug.

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Mutagenicity of paratoluenesulfonamide (PTS)

PTS is a gliclazide degradation impurity which may occur in the dosage form. The mutagenic

potential of PTS is well documented in the literature since this compound is also a degradation

product of saccharin. The following in vitro and in vivo tests support the qualification of this

impurity:

In vitro tests

Ames test

Strains of Salmonella typhimurium (TA 1530/1535/1538/98/100) were tested for doses ≤ 4.10-2

M. No mutagenic effect was observed. The same result was reported for the strains TA

1535/1537/1538/98/100 at doses up to 18000 µg /plate, with and without metabolic activation. In

a ZLM medium (with lower content of glucose and citrate) with a metabolic activator, PTS

induced a slight increase over the revertant frequency in the strain TA 98 at doses ≥ 9600

µg/plate.

SCE test on CHO-K1 cells

Concentrations of 0, 14, 200 and 400 µg /ml did not show any significant difference after a 24-

hour treatment in comparison with the DMSO at a concentration of 50 µg /ml.

Test on human embryo cells

The RSa cells (ouabain-resistant) were exposed to PTS concentrations ≤ 1800 µg /ml. In

comparison with a UV exposure, used as a positive control, no induction of mutation to ouabain-

resistance was observed after a 24-hour treatment.

In vivo tests

Drosophila test

No mutagenic effect was reported with PTS administered by abdominal injection at a dose of 5

mM. In one study, an induction of recessive lethal sex-linked mutation was observed at a

concentration of 2.5 mM.

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Micronucleus test

No significant increase in the micronuclei rate was reported after intraperitoneal or oral

administration (2 x 855 mg/kg) in male and female mice.

Carcinogenicity studies

Specific carcinogenicity studies have not been performed; the following safety data are now

available:

– gliclazide belongs to the chemical class of the phenylsulfonylurea which do not demonstrate

any mutagenic or carcinogenic potential. Its metabolic pathway is consistent with the general

metabolic pathway of the class;

– gliclazide was not associated with any mutagenic action in the numerous studies performed;

– long term toxicity studies did not reveal any evidence of carcinogenicity;

– gliclazide has been studied in several thousands of patients during clinical trials and has been

marketed for numerous years all over the world and in particular in Europe and Japan

without any suspicion of carcinogenicity.

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vascular walls in patients with maturity onset diabetes", Thromb Res 1984; 35(1):19-25 2. BAK J.F., SCHMITZ O., SORENSEN N.S., et al "Postreceptor effects of sulfonylurea on

skeletal muscle glycogen synthase activity in type II diabetic patients", Diabetes 1989;38(11):1343-50

3. BARNETT A.H. "Pathogenesis of diabetic microangiopathy: an overview", Am J Med

1991;90(6A):67S-73S 4. BODANSKY H.J., MEDBACK S., CUDWORTH A.G. et al. "Long term improvement in

insulin response with gliclazide treatment", Diabete Metab 1982;8(4):319-22 5. BOUSKELA E., CYRINO F.Z., CONDE C.M. et al. "Microvascular permeability with

sulfonylureas in normal and diabetic hamsters", Metabolism 1997; 46(12 Suppl 1):26-30 6. CHAN T.K., CHAN V., TENG C.S., YEUNG R.T.T., «Effets du gliclazide et du

glibenclamide sur les fonctions plaquettaires, la fibrinolyse et l’équilibre glycémique chez des diabétiques présentant une rétinopathie», Sem Hop Paris 1982;58(19):1197-1200

7. COLLIER A., WATSON H.H., PATRICK A.W., et al «Effect of glycemic control,

metformin and gliclazide on platelet density and aggregability in recently diagnosed type 2 (non-insulin-dependent) diabetic patients», Diabete Metab 1989; 15(6):420-5

8. DESFAITS A.C., SERRI O., RENIER G. "Gliclazide decreases cell-mediated low-density

lipoprotein (LDL) oxidation and reduces monocyte adhesion to endothelial cells induced by oxidatively modified LDL" Metabolism 1997; 46(10):1150-6

9. DESFAITS A.C., SERRI O., RENIER G."Gliclazide reduces the induction of human

monocyte adhesion to endothelial cells by glycated albumin", Diabetes, Obesity & Metabolism 1999, Mar; 1(2):113-20.

10. DUHAULT J., REGNAULT F., BOULANGER M. et al "Prevention of experimental

obstructions in the retinal microcirculation", Ophtalmologica 1975;170:345-352 11. FLORKOWSKI C.M., RICHARDSON M.R., LE GUEN C. et al. "Effect of gliclazide on

thromboxane B2, parameters of haemostasis, fluorescent IgG and lipid peroxides in non-insulin dependent diabetes mellitus", Diabetes Res 1988; 9(2):87-90

12. FU Z.Z., YAN T., CHEN Y.J. et al. "Thromboxane/prostacyclin balance in type II diabetes: gliclazide effects", Metabolism 1992; 41(5 Suppl 1):33- 5

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13. GAMSTEDT A., FAGERBERG S.E. «Long-term metabolic effects of gliclazide in NIDDM», FADL Publish 1987; 16-19. 14. GOLAY A., BROQUET C., CHABOT V. et al. «Effets métaboliques du gliclazide chez le diabétique de type II. Etude par calorimétrie indirecte», Schweiz Med Wochenschr 1984;114(8):261-264 15. GRAM J., JESPERSEN J., KOLD A. «Effects of an oral antidiabetic drug on the fibrinolytic system of blood in insulin-treated diabetic patients», Metabolism 1988; 37:937-943 16. GRAM J., KOLD A., JESPERSEN J "Rise of plasma t-PA fibrinolytic activity in a group of

maturity onset diabetipatients shifted from a first generation (tolbutamide) to a second generation sulphonylurea (gliclazide)" , J Intern Med 1989; 225(4):241-7

17. GRAM J., JESPERSEN J., DOOIJEWAARD G., et al "The effect of gliclazide on plasma

urokinase-related fibrinolysis. The results from an exploratory study", Fibrinolysis 1994;8(Suppl 2):60-62

18. HARROWER A. "Comparison of diabetic control in type 2 (non-insulin dependent) diabetic

patients treated with different sulphonylureas", Curr Med Res Opin 1985;9:676-680 19. HOICH R.I., NG F.M. "Insulin-potentiating action of gliclazide (Diamicron) ", Pharmacol Res Commun 1986; 18(5):419-430 20. HOSKER J.P., RUDENSKI A.S., BURNETT M.A., et al "Similar reduction of first- and

second- phase B-cell responses at three different glucose levels in type II diabetes and the effect of gliclazide therapy", Metabolism 1989;38(8):767-72

21. INGS R.M.J., CAMPBELL B., GORDON B.H. et al "The effect of renal disease on the

pharmacokinetics of gliclazide in diabetic patients", Br J Clin Pharmacol 1986; 21(5):572- 573

22. JENNINGS P.E., SCOTT N.A., SANIABADI A.R. et al. "Effects of gliclazide on platelet

reactivity and free radicals in type II diabetic patients: clinical assessment", Metabolism 1992; 41(5 Suppl 1):36-9

23. JOHNSON A.B., ARGYRAKI M., THOW J.C. et al. "The effect of sulphonylurea therapy

on skeletal muscle glycogen synthase activity and insulin secretion in newly presenting type 2 (non-insulin-dependent) diabetic patients", Diabet Med 1991; 8(3):243-53

24. KILO C., DUDLEY J., KALB E. "Evaluation of safety and efficacy of gliclazide in non-

Insulin-dependent diabetic patients", Bull Int Diabete Fed 1987; 32(1):27-29 25. KUWASHIMA J. et al. "Inhibition by gliclazide of platelet adhesiveness and aggregation in

the rabbit made diabetic by alloxan", Yakugaku Zasshi 1979; 99(1):59-64

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26. MARCHAND D. et al. "The hypoglycemic effect of a sulfonylurea (gliclazide) in moderate type II diabetes and glucose intolerance is not accompanied by changes in insulin action and insulin binding to erythrocytes", Molecular Physiology 1983;4:83-93

27. MARQUIE G., HADJIISKY P., ARNAUD O. et al. "Development of macroangiopathy in

sand rats (Psammomys obesus), an animal model of non-insulin-dependent diabetes mellitus: effect of gliclazide", Am J Med 1991; 90(6A):55S-61S

28. O’BRIEN R.C., LUO M. "The effects of gliclazide and other sulfonylureas on low-density

lipoprotein oxidation in vitro", Metabolism 1997; 46(12 Suppl 1):22-5 29. PAGANO P.J., GRISWOLD M.C., RAVEL D. et al. "Vascular action of the hypoglycaemic

agent gliclazide in diabetic rabbits", Diabetologia 1998; 41:9-15 30. PHENEKOS C., SIAFAKA-KAPADAI A., TRAPALI M., et al "Effect of gliclazide on

platelet-activating factor-induced platelet aggregation in patients with non-insulin-dependent diabetes mellitus", Metabolism 1992; 41(5 Suppl 1):30-2

31. QUATRARO A., CONSOLI G., CERIELLO A. et al. "Combined insulin and sulfonylurea

therapy in non-insulin-dependent diabetics with secondary failure to oral drugs: a one-year follow-up", Diabete Metab 1986; 12:315-318

32. REGNAULT F. "Gliclazide in the treatment of diabetic retinopathy", Adv Exp Med Biol

1979;119:443-448 33. RENIER G., DESFAITS A.C., SERRI O. "Gliclazide decreases low-density lipoprotein

oxidation and monocyte adhesion to the endothelium", Metabolism 1999, in press 34. RICCIO A., LISATO G., DE KREUTZENBERG S.V. et al. "Gliclazide potentiates

suppression of hepatic glucose production in non-insulin-dependent diabetic patients”, Metabolism 1996; 45(10):1196-202

35. SCOTT N.A., JENNINGS P.E., BROWN J., et al "Gliclazide: a general free radical

scavenger", Eur J Pharmacol 1991; 208(2):175-7 36. SHIMABUKURO M., NAGAMINE F., MURAKAMIK. et al. "Chronic gliclazide treatment

affects basal and post-ischemic cardiac function in diabetic rats", Gen Pharmac 1994; 25(4):697-704

37. TURNER R.C., HOSKER J.P., RUDENSKI A.S. et al. "Similar reduction of first and second

phase B-cell responses at three different glucose levels in type II diabetes, and the effect of gliclazide therapy", Metabolism 1989;38(5):107-110

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38. VESTERGAARD H., WEINREB J.E., ROSEN A.S. et al."Sulfonylurea therapy improves glucose disposal without changing skeletal muscle GLUT4 levels in non insulin-dependent diabetes mellitus subjects: a longitudinal study"J Clin Endocrinol Metab 1995; 80(1):270-5

39. WAJCHENBERG B.J., SANTOMARUO A.T., CHEREM J.J., et al "Effect of gliclazide on

non-insulin dependent diabetes mellitus", Adv Exp Med Biol 1988 40. WAJCHENBERG B.L., SANTOMAURO A.T., GIANNELLA-NETO D., et al "Short - and

long-term gliclazide effects on pancreatic islet cell function and hepatic insulin extraction in non-insulin-dependent diabetes mellitus", Diabetes Res Clin Pract 1992;17(2):89-97

41. WAJCHENBERG B.L., SANTOMAURO A.T., PORRELLI N. "Effect of a sulfonylurea

(gliclazide) treatment on insulin sensitivity and glucose-mediated glucose disposal in patients with non-insulin-dependent diabetes mellitus (NIDDM)", Diabetes Res Clin Pract 1993;20(2):147-54

42. WARD G., HARRISON L.C., PROIETTO J., et al "Gliclazide therapy is associated with

potentiation of postbinding insulin action in obese, non-insulin-dependent diabetic subjects", Diabetes 1985; 34(3):241-5

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14, 2008.

IMPORTANT: PLEASE READ

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PART III: CONSUMER INFORMATION

PrGLICLAZIDE MR Gliclazide modified release tablets

This leaflet is part III of a three-part "Product Monograph" published when GLICLAZIDE MR was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about GLICLAZIDE MR. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION What the medication is used for: GLICLAZIDE MR is used to lower blood glucose level in adult patients with type 2 diabetes mellitus in addition to proper diet, exercise and weight reduction. What it does: GLICLAZIDE MR belongs to the family of hypoglycemic (antidiabetic) drugs and part of a sub family of medicines called sulfonylureas. It helps improving insulin secretion in the body. When it should not be used: GLICLAZIDE MR is contraindicated (must not be taken):

• If you are allergic or hypersensitive to gliclazide, other sulfonylureas, sulfonamides, or to any of the excipients of this product.

• If you have unstable and/or insulin-dependant diabetes mellitus, juvenile diabetes (type I diabetes),

diabetes ketoacidosis, diabetes pre-coma and coma. • If you are in stressful conditions such as serious

infection, trauma or surgery. • If you have severe liver disease or renal impairment. • If you receive treatment with miconazole. • If you are pregnant and/or breast-feeding.

What the medicinal ingredient is: Gliclazide What the important nonmedicinal ingredients are: Colloidal silicon dioxide, hydroxypropyl methylcellulose and stearic acid What dosage forms it comes in: GLICLAZIDE MR comes in modified release tablets. Each tablet contains 30 mg of gliclazide.

WARNINGS AND PRECAUTIONS BEFORE you use GLICLAZIDE MR talk to your doctor or pharmacist if:

GLICLAZIDE MR may cause low blood sugar (hypoglycemia). You should ask your doctor, pharmacist or diabetes educator about symptoms of low blood sugar and what to do if you experience these symptoms. You should also test your blood sugar as instructed by your doctor. Before you use GLICLAZIDE MR talk to your doctor or pharmacist if:

• you have or have had liver, kidney disease • you are pregnant or planning to get pregnant • you are breast-feeding

GLICLAZIDE MR is not recommended for use in children under 18 years of age. Driving and Operating Machinery: Alertness and reactions may be impaired due to low blood sugar (hypoglycemia), especially at beginning of the treatment. This may affect your ability to drive or to operate machinery.

INTERACTIONS WITH THIS MEDICATION Drugs that may interact with GLICLAZIDE MR include: other antidiabetic agents (insulin, alpha glucosidase inhibitors, biguanides), long-acting sulfonamides, tuberculostatics, NSAIDs, fibrates, monoamine oxidase inhibitors, salicylates, probenecid, beta-blockers, azole antifungal agents (miconazole and fluconazole via oral and parenteral preparations), H2 receptor antagonists and angiotensin converting enzyme inhibitors, anticoagulants, and barbiturates. Certain drugs tend to induce hyperglycemia and may lead to loss of blood sugar control. These include diuretics (thiazides, furosemide), corticosteroids, oral contraceptives (estrogen plus progestogen), chlorpromazine, ritodrine, salbutamol, terbutaline, danazol and nicotinic acid in pharmacologic doses. Do not take any other medicine, unless prescribed or approved by your doctor. If you require medical assistance, inform the medical practitioner that you are taking GLICLAZIDE MR. Avoid drinking alcoholic beverages and taking medicines containing alcohol while you are taking GLICLAZIDE MR as it can lead to drop in blood sugar (hypoglycemia).

PROPER USE OF THIS MEDICATION Usual dose: The recommended starting dose of GLICLAZIDE MR is 1 tablet per day (30 mg), even in elderly patients (over 65 years old). The daily dose should not exceed 120 mg. Take GLICLAZIDE MR once daily at breakfast. Swallow the tablet whole with a glass of water. The tablet must not be chewed or crushed.


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You will test your sugar level as directed by your physician to make sure that your blood sugar is being controlled. Your physician should check your progress at regular visits, especially during the first few weeks that you take this medicine. Overdose: Taking too much of any medicines can be dangerous. If you take too many GLICLAZIDE MR tablets at once, call your doctor or go to the emergency room of your local hospital or to the nearest Poison Control Centre. Missed Dose: If you miss a dose of this medicine, you should not double the dose on the next day.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM As with any type of medication, GLICLAZIDE MR is associated with some side effects. It may, however, affect different people in different ways. The more frequently side effects reported during clinical trials with GLICLAZIDE MR were hypoglycemia (low blood sugar) and indigestion or stomach upsets (diarrhea, constipation, nausea, vomiting, gastritis, flatulence, dyspepsia). You should know that the usual signs of low blood sugar level (hypoglycemia) are: anxious feeling, drowsiness, chills, cold sweats, confusion, cool pale skin, difficulty in concentration, excessive hunger, fast heartbeat, headache, nausea, nervousness, shakiness, unsteady walk, unusual tiredness or weakness. If you recognize by some of these signs of the drop in blood sugar, immediately eat or drink something containing sugar and notify your doctor without delay. Good sources of sugar are: orange juice, corn syrup, honey, or sugar cubes or table sugar (dissolved in water).

SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM

Talk with your doctor or

pharmacist

Symptom / effect

Only if severe

In all cases

Stop taking drug and call your doctor or

pharmacist

SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM

Talk with your doctor or

pharmacist

Common

Low blood sugar level (hypoglycemia) The usual signs are : anxious feeling, drowsiness, chills, cold sweats, confusion, cool pale skin, difficulty in concentration, excessive hunger, fast heartbeat, headache, nausea, nervousness, shakiness, unsteady walk, unusual tiredness or weakness

√

Uncommon

Unexplained fever chills or sore throat. Unusual bleeding or bruising. Yellowing of skin or eyes, dark-coloured urine or light-coloured bowel movements. Skin rash or hives. Oedema, swelling of the legs or unexpected weight gain.

√

√

This is not a complete list of side effects. For any unexpected effects while taking GLICLAZIDE MR, contact your doctor or pharmacist.


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HOW TO STORE IT Keep out of reach or sight of children. Store at room temperature (15°C - 25°C). Protect from humidity.

REPORTING SUSPECTED SIDE EFFECTS You can report any suspected adverse reactions associated with the use of health products to the Canada Vigilance Program by one of the following ways: • Report online at www.healthcanada.gc.ca/medeffect • Call toll-free 1-866-234-2345 • Complete a Canada Vigilance Reporting Form and: - Fax toll-free to 1-866-678-6789, or - Mail to: Canada Vigilance Program Health Canada Postal Locator 0701D Ottawa, ON K1A 0K9 Postage paid labels, Canada Vigilance Reporting Form and the adverse reaction reporting guidelines are available on the MedEffect™ Canada Web site at: www.healthcanada.gc.ca/medeffect NOTE: Should you require information related to the management of side effects, contact your health professional. The Canada Vigilance Program does not provide medical advice.

MORE INFORMATION For more information, please contact your doctor, pharmacist or other healthcare professional. This leaflet plus the full product monograph, prepared for health professionals, can be obtained by contacting the sponsor, AA Pharma Inc., at 1-877-998-9097. This leaflet was prepared by AA Pharma Inc. Last revised: June 25, 2010

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